Administration of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid for the treatment of dermatological disorders

ABSTRACT

Dermatological disorders having an inflammatory or proliferative component are treated with pharmaceutical compositions containing on the order of 0.3% by weight of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid (adapalene) or salt thereof, formulated into pharmaceutically acceptable media therefor, advantageously topically applicable gels, creams or lotions.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 15/175,188, filed Jun. 7, 2016, now allowed, which is acontinuation of co-pending U.S. patent application Ser. No. 14/222,185,filed Mar. 21, 2014, now U.S. Pat. No. 9,381,179, which is acontinuation of U.S. patent application Ser. No. 12/902,972, filed Oct.12, 2010, now U.S. Pat. No. 8,703,820, which is a continuation of U.S.patent application Ser. No. 12/437,008, filed May 7, 2009, now U.S. Pat.No. 7,834,060, which is a continuation of U.S. patent application Ser.No. 10/937,612, filed Sep. 10, 2004, now U.S. Pat. No. 7,579,377, whichis a continuation of PCT/EP03/03246 filed Mar. 12, 2003, and designatingthe United States (published in English on Sep. 18, 2003 as WO 03/075908A1), which claims benefit of U.S. Provisional Application No.60/370,223, filed Apr. 8, 2002, and also claims priority under 35 U.S.C.§ 119 of FR-02/03070, filed Mar. 12, 2002, each earlier applicationbeing hereby expressly incorporated by reference and each assigned tothe assignee hereof.

CROSS REFERENCE TO OTHER RELATED APPLICATIONS

See also co-pending U.S. patent application Ser. No. 12/103,182, filedApr. 15, 2008, now U.S. Pat. No. 7,838,558, which is a divisionalapplication of earlier filed co-pending U.S. patent application Ser. No.10/937,612, filed Sep. 10, 2004, now U.S. Pat. No. 7,579,377, and claimsthe same domestic and foreign priority as claimed herein; and co-pendingU.S. patent application Ser. No. 12/772,861, filed May 3, 2010, which isa division of U.S. patent application Ser. No. 11/494,693, filed Jul.28, 2006, now U.S. Pat. No. 7,737,181, which is a continuation-in-partof earlier filed co-pending U.S. patent application Ser. No. 10/937,612filed Sep. 10, 2004, and claims the same domestic and foreign priorityas claimed herein; both of said applications also expressly incorporatedby reference herein and assigned to the assignee hereof.

BACKGROUND OF THE INVENTION Technical Field of the Invention

The present invention relates to the administration to individuals inneed of such treatment of6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid, the chemicalstructure of which is as follows:

in pharmaceutical compositions, in particular dermatologicalcompositions, for the treatment of dermatological ailments/afflictionshaving an inflammatory or proliferative component.

Description of Background and/or Related and/or Prior Art

6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthanoic acid (hereinafterreferred to as adapalene) is a retinoid derived from naphthoic acid,having anti-inflammatory properties. This molecule has been the subjectof development for the topical treatment of common acne and dermatosessensitive to retinoids.

Adapalene is described in EP-0,199,636, and a process for synthesizingsame is described in EP-0,358,574, both assigned to the assignee hereof.

The assignee hereof markets adapalene formulated at a weightconcentration of 0.1% in the form of an alcoholic lotion, an aqueous geland a cream. These compositions are suited for the treatment of acne.

Finally, adapalene is described as having a beneficial action onphotodamaged skin (Photographic assessment of the effects of adapalene0.1% and 0.3% gels and vehicle on photodamaged skin. M. Goldfarb et al.,Clinical Dermatology, Vienna, Austria, May 2000).

SUMMARY OF THE INVENTION

Novel pharmaceutical compositions have now been developed containingadapalene at a weight concentration of 0.3% formulated intopharmaceutically acceptable media therefor, useful for the treatment(regime or regimen) of dermatological ailments, conditions orafflictions having an inflammatory or proliferative component.Specifically, it has now surprisingly been shown that, in addition toexhibiting better therapeutic efficacy compared to known compositions,the compositions according to the invention exhibits good tolerance,comparable to those of the known compositions with a lower concentrationof active principle.

The results regarding tolerance observed in trials relating tophoto-damaged skin (indication “photodamage”), obtained on individualson average 65 years old, could not be exploited in the context of thepresent invention. Specifically, as regards use of adapalene on youngindividuals (in particular regarding acne with populations of teenagersor young adults), the skin exhibits very different physiopathologicalcharacteristics (presence of many lesions, in particular inflammatorylesions, modifying skin permeability, hypercornification of thefollicular channel, immuno response, bacterial colonization of the skin(P. acnes), sebaceous hyperplasia with hyperseborrhea).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating regression in the number of total lesionsfor 0.30% adapalene gel, as compared to 0.10% adapalene gel and the gelvehicle without active ingredient, over a 12-week treatment period ingroups of patients suffering from acne.

FIG. 2 is a graph illustrating regression in the number of inflammatorylesions for 0.30% adapalene gel, as compared to 0.10% adapalene gel andthe gel vehicle without active ingredient, over a 12-week treatmentperiod in groups of patients suffering from acne.

FIG. 3 is a graph illustrating regression in the number ofnon-inflammatory lesions for 0.30% adapalene gel, as compared to 0.10%adapalene gel and the gel vehicle without active ingredient, over a12-week treatment period in groups of patients suffering from acne.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

Thus, the present invention features formulating6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid (adapalene), orits salts, into pharmaceutical compositions useful for the treatment ofdermatological ailments, conditions or afflictions having aninflammatory or proliferative component, such pharmaceuticalcompositions comprising 0.3% by weight of adapalene relative to thetotal weight of the composition.

The term “adapalene salts” is intended to mean the salts formed with apharmaceutically acceptable base, in particular organic bases such assodium hydroxide, potassium hydroxide and aqueous ammonia, or organicbases such as lysine, arginine or N-methylglucamine.

The term “adapalene salts” is also intended to mean the salts formedwith fatty amines such as dioctylamine and stearylamine.

The administration of the compositions according to the invention may becarried out enterally, parenterally, topically or occularly.

The pharmaceutical compositions according to the invention arepreferably administered topically.

Enterally, the pharmaceutical composition may be in the form of tablets,gelatin capsules, dragées, syrups, suspensions, solutions, powders,granules, emulsions, or suspensions of microspheres or nanospheres or oflipid or polymeric vesicles for controlled release. Parenterally, thepharmaceutical composition may be in the form of solutions orsuspensions for infusion or for injection.

Topically, the pharmaceutical compositions according to the inventionare more particularly suited for treatment of the skin and the mucousmembranes, and may be in the form of ointments, creams, milks, pomades,powders, impregnated pads, solutions, gels, sprays, lotions orsuspensions. They may also be in the form of suspensions of microspheresor nanospheres or of lipid or polymeric vesicles, or of polymericpatches and hydrogels for controlled release. These compositions fortopical application may be in anhydrous form, in aqueous form or in theform of an emulsion.

In a preferred embodiment of the invention, the pharmaceuticalcomposition according to the invention is in the form of a gel, a creamor a lotion.

In particular, the pharmaceutical composition may be an aqueous gelcontaining in particular one or more ingredients selected from amongCarbomer 940 (BF Goodrich, Carbopol 980) and propylene glycol, or acream containing in particular one or more ingredients selected fromamong perhydrosqualene, cyclomethicone, PEG-20 methyl glucosesequistearate and methyl glucose sequistearate, or a polyethyleneglycol-based alcoholic lotion.

The pharmaceutical compositions according to the invention may alsocontain inert additives or combinations of these additives, such as

-   -   wetting agents;    -   flavor enhancers;    -   preservatives such as para-hydroxybenzoic acid esters;    -   stabilizers;    -   moisture regulators;    -   pH regulators;    -   osmotic pressure modifiers;    -   emulsifiers;    -   UV-A and UV-B screening agents;    -   and antioxidants, such as α-tocopherol, butylhydroxyanisole or        butylhydroxytoluene, superoxide dismutase, ubiquinol or certain        metal chelating agents.

Of course, those skilled in the art will take care to select theoptional compound(s) to be added to these compositions in such a waythat the advantageous properties intrinsically associated with thepresent invention are not, or are not substantially, adversely affectedby the envisaged addition.

The formulation of adapalene into pharmaceutical compositions accordingto the invention is especially intended for the treatment ofdermatological ailments, conditions and afflictions having aninflammatory or proliferative component, selected from the groupconsisting of:

-   -   common acne, comedones, polymorphous acne, nodulocystic acne,        acne conglobata, secondary acne such as solar, drug-related or        occupational acne;    -   widespread and/or severe forms of psoriasis, ichtyoses and        ichtyosiform states;    -   Darier's disease;    -   actinic keratoses;    -   palmo plantar keratoderma and keratosis pilaris;    -   leucoplasias and leucoplasiform states, lichen planus;    -   any benign or malignant, severe and extensive dermatological        preparations.

The compositions according to the invention are particularly suitablefor the treatment of acne, such as common acne, and in particular forthe treatment of common acne of moderate to moderately severe intensity.

Various formulations of compositions comprising 0.3% of adapalene willnow be given, it being understood that same are intended only asillustrative and in nowise limitative. Also given are results showingthe therapeutic effects of the compositions according to the inventionand the good tolerance to same by the treated patients.

In said examples to follow, all parts and percentages are given byweight, unless otherwise indicated.

EXAMPLE 1—FORMULATION FOR TOPICAL ADMINISTRATION

In this example, various specific topical formulations comprising 0.3%of adapalene are illustrated.

The adapalene of the present example is provided by Sylachim, DivisionFinorga (product reference CF9611996).

(a) Cream:

Adapalene 3 mg Carbomer 934 (BF Goodrich 4.5 mg Carbopol 974) Disodiumedetate 1 mg PEG methyl glucose sesquistearate 35 mg Methyl glucosesesquistearate 35 mg Glycerol 30 mg Methyl paraben 2 mg Cyclomethicone130 mg Perhydrosqualene 60 mg Phenoxyethanol 5 mg Propyl paraben 1 mgSodium hydroxide quantity required for pH 6.5 +/− 0.3 Purified waterq.s. 1 g

(b) Lotion:

Adapalene 3 mg PEG 400 700 mg Ethanol q.s. 1 g

(c) Aqueous Gel:

Adapalene 3 mg Carbomer 940 (BF Goodrich 11 mg Carbopol 980) Disodiumedetate 1 mg Methyl paraben 2 mg Poloxamer 124 2 mg Propylene glycol 40mg Sodium hydroxide: amount required to obtain a pH 5.0 +/− 0.3 Purifiedwater q.s. 1 g

EXAMPLE 2—EFFECTIVENESS OF 0.3% ADAPALENE GEL AND COMPARISON WITH THE0.1% ADAPALENE GEL

Tests were carried out on a population consisting of patients sufferingfrom acne. In this population, three groups were differentiated; thefirst received a daily topical application of the 0.3% adapalene gel,the second a daily topical application of the 0.1% adapalene gel in thesame vehicle, and the third is a control group which receives a dailytopical application of the gel corresponding to the composition of thefirst two gels but containing no active agent.

FIGS. 1 to 3 provide the results obtained in terms of regression of thenumber of lesions according to their nature.

These observations lead to the following conclusions:

-   -   the 0.3% adapalene gel acts more rapidly than the 0.1% adapalene        gel; specifically, from the fourth week of treatment, a        difference is noted between the effectiveness of the 0.1%        adapalene gel and the 0.3% adapalene gel;    -   the 0.3% adapalene gel produces a clearly greater therapeutic        effect after 8 weeks of treatment.

EXAMPLE 3—TOLERANCE REGARDING THE 0.3% ADAPALENE GEL

1. Measurement of the Plasma Concentration of Adapalene:

Eight individuals suffering from common acne of medium to moderatelysevere intensity are treated for 10 days with 2 g of 0.3% adapalene gelapplied daily over 1000 cm² of skin to be treated (face, chest andback).

Blood samples are taken on the days 1, 2, 4, 6, 8 and 10. During day 10,and following the final application, samples are taken at 1, 2, 6, 8,10, 12, 16 and 24 hours.

The plasma concentration of total adapalene (free and conjugated) inthese samples is determined using the following protocol:

-   -   enzymatic hydrolysis with a mixture of β-glucurodinase and        arylsulfatase;    -   liquid-liquid extraction;    -   passage through HPLC (high performance liquid chromatography);        and then fluorometric detection.

This method makes it possible to detect a minimum concentration of 0.15ng/ml and permits quantification of the adapalene for a minimumconcentration of 0.25 ng/ml.

CONCLUSION

The plasma concentrations of adapalene measured after 10 days oftreatment are very low and confirm the safety of daily use of the 0.3%adapalene gel.

2 a) Clinical Observation of the Side Effects Caused by TopicalAdministration of the 0.3% Adapalene Gel:

Two types of observation could be made:

-   -   firstly, monitoring of the patients treated within the framework        of point 1 of the present Example 3 made it possible to note        that tolerance to the 0.3% adapalene gel was good for all        patients. They all showed signs of dryness of the skin and of        desquamation with a maximum on the seventh day of treatment,        these symptoms then decrease up to the end of the treatment.

2 b) Furthermore, Reference May Also Be Made to the Tests Described inExample 2 Above:

In parallel to the measurements of effectiveness, the experimentersrecorded the possible side effects caused, firstly, by topicalapplication of the 0.3% adapalene gel and those caused, secondly, byapplication of the 0.1% adapalene gel; finally, the same observationswere made on a control population to which a gel without activeprinciple was administered.

These observations are reported in the table below.

Local undesirable 0.3% adapalene 0.1% adapalene Vehicle gel effects gel(N = 70) gel (N = 70) (N = 74) Skin and secondary 31 (44.3%) 28 (40.0%)5 (6.8%) structures (nails, hair) Dry skin 16 (22.9%) 13 (18.6%) 2(2.7%) Erythema 8 (11.4%) 3 (4.3%) 0 (0.0%) Skin discomfort 8 (11.4%) 7(10.0%) 0 (0.0%) Desquamation 6 (8.6%) 5 (7.1%) 0 (0.0%) Dermatitis 3(4.3%) 1 (1.4%) 0 (0.0%) Pruritus 3 (4.3%) 1 (1.4%) 1 (1.4%) Irritantdermatitis 2 (2.9%) 7 (10.0%) 0 (0.0%) Local allergic reactions 1 (1.4%)0 (0.0%) 0 (0.0%) Pediculosis 1 (1.4%) 0 (0.0%) 0 (0.0%) Contactdermatitis 1 (1.4%) 0 (0.0%) 0 (0.0%) Insolation 1 (1.4%) 3 (4.3%) 1(1.4%) Burning sensation 1 (1.4%) 0 (0.0%) 0 (0.0%) Urticaria 1 1.4%) 0(0.0%) 0 (0.0%) Infection 1 (1.4%) 0 (0.0%) 0 (0.0%) Excoriation 0(0.0%) 0 (0.0%) 1 (1.4%) Eczema 0 (0.0%) 0 (0.0%) 1 (1.4%) Oedema 0(0.0%) 1 (1.4%) 0 (0.0%)

From this table, it is noted that the occurrence of undesirable sideeffects is statistically the same for the two gels with the differentconcentrations of active agent. The intensity of the undesirable sideeffects is average, which leads to the conclusion that the two gels arewell-tolerated by the patients.

On the basis of these observations, it may be concluded that patientssuffering from common acne can be treated with 0.3% adapalene gel, suchan exposure to adapalene being described as weak or very weak underclinical conditions.

It therefore ensues from these various studies that a pharmaceuticalcomposition containing 0.3% of adapalene exhibits a benefit/risk ratiowhich makes it particularly suitable for the treatment of dermatologicalmaladies having an inflammatory or proliferative component, and inparticular, common acne.

Each patent, patent application, publication and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A method for eliciting an early onset of actionin regression of non-inflammatory lesions in treating common acneafflicting an individual's skin, the individual being in need of suchtreatment, comprising topically administering daily to said individualan anti-acne effective amount of a pharmaceutical composition whichconsists essentially of: (1) 0.3% by weight of6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (adapalene) or saltthereof; (2) one or more ingredients selected from the group consistingof carbomer 940, carbomer 934, disodium edetate, methyl paraben,propylene glycol, PEG methyl glucose sesquistearate, PEG 400, methylglucose sesquistearate, cyclomethicone, perhydrosqualene, propylparaben, glycerol, sodium hydroxide, ethanol and phenoxyethanol; (3)water; and (4) optionally, one or more additive selected from the groupconsisting of wetting agents, pH regulators, osmotic pressure modifiers,emulsifiers, UV-A and UV-B screening agents and antioxidants, whereinsaid composition is formulated into a pharmaceutically acceptable mediumtherefor, said composition being a gel or a cream, said early onset ofaction occurring by two weeks after treatment begins and beingdemonstrated by regression of non-inflammatory lesions after two weeksof treatment greater than that demonstrated by vehicle alone or by asimilar composition comprising 0.1% by weight of adapalene after twoweeks of treatment.